John B Mulliken’s research while affiliated with Boston Children's Hospital and other places

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Publications (660)


R(+) Propranolol decreases lipid accumulation in haemangioma-derived stem cells
  • Article

November 2024

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11 Reads

British Journal of Dermatology

Jerry Wei Heng Tan

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Infantile hemangioma (IH), often treated with propranolol, is a benign vascular tumor that undergoes a spontaneous involution to a fibrofatty residuum. We investigated how R(+) propranolol, the non-beta blocker enantiomer of racemic propranolol, affects lipid accumulation and adipogenesis in IH. This was motivated by our previous work showing R(+) propranolol can block blood vessel formation in a pre-clinical model of IH. Our findings suggest a novel regulatory role for the R(+) propranolol in modulating lipid accumulation in HemSC. This highlights a novel role of R(+) propranolol in the involuting phase of IH and a strategy to reduce fibrofatty residua in IH.


Once-a-Day Administration of R(+) Propranolol Is Sufficient to Block Vasculogenesis in a Xenograft Model of Infantile Hemangioma

August 2024

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5 Reads

Journal of Vascular Anomalies

Objective Infantile hemangioma (IH) is a benign vascular tumor that occurs in 5% of infants, predominantly in female and preterm neonates. Propranolol is the mainstay of treatment for IH. Given the short half-life of propranolol regarding β-adrenergic receptor inhibition as well as its side effects, propranolol is administered to infants 2–3 times daily with 1 mg/kg/dose. We previously demonstrated propranolol inhibits IH vessel formation via an effect of its R(+) enantiomer on the endothelial-specific transcription factor SRY box 18 (SOX18). In light of this, we hypothesized that R(+) propranolol inhibition of SOX18 is long-lived compared to the beta-blocker effects, and therefore administration of R(+) propranolol once a day would be sufficient to block IH vessel formation. Methods We tested the effect of 1 dose versus 2 doses of R(+) propranolol in a xenograft model of IH wherein patient-derived hemangioma stem cells were implanted subcutaneously into nude mice. Mice were treated for 7 days with 2 × 12.5 mg/kg/d (n = 12) versus 1 × 25 mg/kg/d (n = 14) as well as phosphate-buffered saline (vehicle control) (n = 16) via intraperitoneal injections. The doses were estimated to correlate with those given to infants with IH. Results Treatment with R(+) propranolol significantly inhibited vasculogenesis in our IH xenograft model at both 2 × 12.5 mg/kg/d and 1 × 25 mg/kg/d, compared to vehicle controls. No significant difference was observed between the 2 treatment regimens. Conclusion Our results suggest implications for the clinical management of infants with IH: Administration of R(+) propranolol can possibly minimize or omit concerning β-adrenergic side effects while only requiring 1 dose per day.


R(+) Propranolol decreases lipid accumulation in hemangioma-derived stem cells

July 2024

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23 Reads

Background Infantile hemangioma (IH) is a benign vascular tumor that undergoes an initial rapid growth phase followed by spontaneous involution. A fibrofatty residuum remains in many tumors and often necessitates resection. We recently discovered that R(+) propranolol, the non-β blocker enantiomer, inhibits blood vessel formation of IH patient-derived hemangioma stem cells (HemSC) xenografted in mice. HemSC are multipotent cells with the ability to differentiate into endothelial cells, pericytes, and adipocytes. Objectives We investigated how R(+) propranolol affects HemSC adipogenic differentiation and lipid accumulation, in vitro and in a preclinical murine model for IH. Methods We conducted a 10-day adipogenesis assay on 4 IH patient-derived HemSCs. Oil Red O (ORO) staining was used to identify the onset and level of lipid accumulation in HemSC while quantitative real-time polymerase chain reaction was conducted to determine the temporal expression of key factors implicated in adipogenesis. 5-20µM R(+) propranolol treatment was added to HemSC induced to undergo adiogenesis for 4 and 8 days, followed by quantification of lipid-stained areas and transcript levels of key adipogenic factors. We immunostained for lipid droplet-associated protein Perilipin 1 (PLIN1) in HemSC-xenograft sections from mice treated with R(+) propranolol and quantified the area using ImageJ. Results We found that different patient-derived HemSC exhibit a robust and heterogenous adipogenic capacity when induced for adipogenic differentiation in vitro. Consistently across four IH patient-derived HemSC isolates, R(+) propranolol reduced ORO-stained areas and lipoprotein lipase (LPL) transcript levels in HemSC after 4 and 8 days of adipogenic induction. In contrast, R(+) propranolol had no significant inhibitory effect on transcript levels encoding adipogenic transcription factors. In a pre-clinical HemSC xenograft model, PLIN1-positive area was significantly reduced in xenograft sections from mice treated with R(+) propranolol, signifying reduced lipid accumulation. Conclusions Our findings suggest a novel regulatory role for the R(+) enantiomer of propranolol in modulating lipid accumulation in HemSC. This highlights a novel role of R(+) propranolol in the involuting phase of IH and a strategy to reduce fibrofatty residua in IH. What is already known about this topic? Propranolol is the mainstay treatment for infantile hemangioma (IH), the most common tumor of infancy, but its use can be associated with concerning β-blocker side effects. R(+) propranolol, the enantiomer largely devoid of β-blocker activity, was recently shown to inhibit endothelial differentiation of hemangioma-derived stem cells (HemSC) in vitro and reduce blood vessel formation in a HemSC-derived xenograft murine model of IH. What does this study add? R(+) propranolol inhibits lipid accumulation in HemSC in vitro. R(+) propranolol does not affect mRNA transcript levels of key adipogenic transcription factors in differentiating HemSC in vitro. R(+) propranolol reduces lipid accumulation in a pre-clinical xenograft murine model of IH. What is the translational message? The R(+) enantiomer of propranolol could be advantageous in terms of reduction in β-adrenergic side effects and fibrofatty tissue formation in the involuting phase of IH. Less fibrofatty residua might reduce the need for surgical resection. Disfigurement and associated psychosocial impacts might be improved in this young patient cohort.


Figure 1. Life cycle, cellular components, and molecular players in IH. (A) Series of clinical images of a healthy female newborn (left) and the same individual at 5 months of age with an extensive facial and upper airway IH requiring tracheostomy (middle). This patient was treated with systemic corticosteroids, which was the mainstay of treatment at the time. The final image shows the patient at 5 years of age, with the IH in the involuted phase (right). Reproduced with permission from Elsevier (131). (B) H&E staining of proliferating and involuting IH demonstrates the differences in cellularity and vessel morphology in both phases in the IH cycle. Scale bars: 100 μm. Reproduced with permission from Angiogenesis (132). (C) Schematic of hemangioma stem cells, hemangioma endothelial cells, and hemangioma pericytes and molecular features of each cell type. Adapted with permission from the British Journal of Dermatology (133).
Figure 2. Propranolol targets the endothelial transcription factor SOX18 to inhibit vasculogenesis in IH. (A) The R(+) enantiomers of propranolol and atenolol and the small-molecule SOX18 inhibitor Sm4 inhibit hemangioma stem cell (HemSC) to hemangioma endothelial cell (HemEC) differentiation in vitro and ability of HemSCs to form de novo vessels in vivo. R(+) propranolol inhibits SOX18 by interfering with its search patterns along chromatin, its homodimer (SOX18:SOX18) or heterodimer formation with RBPJ (SOX18:RBPJ), and its transcriptional activation of target genes. In patient tissue, SOX18 expression (magenta) coincides with nuclei (blue) and colocalizes with UEA (gray), indicating its presence in endothelial cells of proliferating IH tissue. The inset confocal image was acquired with a Zeiss LSM 880 by AH. Scale bar: 10 μm. Adapted with permission from the Journal of Clinical Investigation (86). (B) Summary of differential drug mechanisms of action inhibiting IH vasculogenesis. Corticosteroids inhibit the expression of VEGF-A; sirolimus reduces stemness and self-renewal of HemSC; R(+) propranolol and R(+) atenolol act on SOX18 as described in A. SOX18 expression increases over the course of HemSC to HemEC differentiation.
Infantile hemangioma: the common and enigmatic vascular tumor
  • Literature Review
  • Full-text available

April 2024

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84 Reads

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8 Citations

The Journal of clinical investigation

Infantile hemangioma (IH) is a benign vascular tumor that occurs in 5% of newborns. The tumor follows a life cycle of rapid proliferation in infancy, followed by slow involution in childhood. This unique life cycle has attracted the interest of basic and clinical scientists alike as a paradigm for vasculogenesis, angiogenesis, and vascular regression. Unanswered questions persist about the genetic and molecular drivers of the proliferating and involuting phases. The beta blocker propranolol usually accelerates regression of problematic IHs, yet its mechanism of action on vascular proliferation and differentiation is unclear. Some IHs fail to respond to beta blockers and regrow after discontinuation. Side effects occur and long-term sequelae of propranolol treatment are unknown. This poses clinical challenges and raises novel questions about the mechanisms of vascular overgrowth in IH.

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Immunohistochemical Expression of Lymphatic Endothelial Markers in Blue Rubber Bleb Nevus Syndrome

March 2024

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9 Reads

Pediatric and Developmental Pathology

Introduction Blue rubber bleb nevus syndrome (BRBNS) is an uncommon vascular anomaly characterized by multifocal cutaneous, visceral, and other soft tissue or solid organ venous malformations. We observed that BRBNS lesions express immunohistochemical markers of lymphatic differentiation. Methods BRBNS histopathologic specimens assessed at our institution during the past 27 years were reviewed. Slides from 19 BRBNS lesions were selected from 14 patients (9 cutaneous, 9 gastrointestinal, and 1 hepatic). We recorded the involved anatomical compartments and presence/absence of thrombi or vascular smooth muscle. Immunohistochemical endothelial expression of PROX1 (nuclear) and D2-40 (membranous/cytoplasmic) was evaluated semi-quantitatively. Results Endothelial PROX1 immunopositivity was noted in all specimens; the majority (89.5%) demonstrated staining in more than 10% of cells. D2-40 immunopositivity was present in one-third (33%) of cutaneous lesions and only 1 gastrointestinal lesion. Conclusion Endothelial cells in BRBNS almost always express 1 or more immunohistochemical markers of lymphatic differentiation.


Elastic Chain Premaxillary Retraction Appliance Does Not Increase Inter-Canthal Dimension in Patients with Bilateral Cleft Lip and Palate

March 2024

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8 Reads

The Cleft Palate-Craniofacial Journal

Objective To determine if the elastic chain premaxillary retraction (ECPR) appliance increases inter-medial and inter-lateral canthal dimension in patients with bilateral complete cleft lip and palate (BCLP). Design Retrospective cohort study. Setting Specialized tertiary care facility. Patients, Participants 126 patients with BCLP; 75 had ECPR, 51 had no pre-surgical manipulation. Interventions Three-dimensional facial photographs were obtained prior to insertion of appliance (T0), post-appliance therapy prior to appliance removal/labial repair (T1), and several months after labial repair (T2) for a longitudinal ECPR group, and were obtained after age 4 years (T3) for a non-longitudinal ECPR group and for the non-ECPR group. Main Outcome Measures Inter-medial and inter-lateral canthal dimension (en-en, ex-ex) was determined for all groups/time-points. Measurements were compared between groups and to norms. Results The mean en-en and ex-ex was 32.6 ± 3.2 mm and 84.4 ± 6.3 mm for the ECPR group and 33.5 ± 3.1 mm and 86.7 ± 7.2 mm for the non-ECPR group at T3. Inter-medial and inter-lateral canthal dimensions were significantly greater than normal ( P < .05) in both groups; there was no significant difference between groups ( P > .05). The mean en-en and ex-ex for the Longitudinal ECPR group was 27.5 ± 2.4 mm and 66.7 ± 3.7 mm at T0, 29.6 ± 2.4 mm and 70.4 ± 2.9 mm at T1, and 29.2 ± 2.3 mm and 72.3 ± 3.8 mm at T2. en-en and ex-ex increased significantly from T0-T1 ( P < .05), decreased at T2 ( P > .05) and was significantly larger than normal at all time-points ( P < .05). Conclusions Inter-medial and inter-lateral canthal dimension increased after ECPR but returned to baseline growth trajectory. These dimensions were above normal at all time-points. There was no difference between those that did and did not have dentofacial orthopedic manipulation.


Divergent growth of the transient brain compartments in fetuses with nonsyndromic isolated clefts involving the primary and secondary palate

February 2024

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47 Reads

Cerebral Cortex

Cleft lip/palate is a common orofacial malformation that often leads to speech/language difficulties as well as developmental delays in affected children, despite surgical repair. Our understanding of brain development in these children is limited. This study aimed to analyze prenatal brain development in fetuses with cleft lip/palate and controls. We examined in utero MRIs of 30 controls and 42 cleft lip/palate fetal cases and measured regional brain volumes. Cleft lip/palate was categorized into groups A (cleft lip or alveolus) and B (any combination of clefts involving the primary and secondary palates). Using a repeated-measures regression model with relative brain hemisphere volumes (%), and after adjusting for multiple comparisons, we did not identify significant differences in regional brain growth between group A and controls. Group B clefts had significantly slower weekly cerebellar growth compared with controls. We also observed divergent brain growth in transient brain structures (cortical plate, subplate, ganglionic eminence) within group B clefts, depending on severity (unilateral or bilateral) and defect location (hemisphere ipsilateral or contralateral to the defect). Further research is needed to explore the association between regional fetal brain growth and cleft lip/palate severity, with the potential to inform early neurodevelopmental biomarkers and personalized diagnostics.


Figure 4. Nuclear co-localization of SOX18 and SREBP2 in proliferating phase and regrowing IH indicate active MVP. (A-D) Human age-matched skin, proliferating IH, involuting IH and regrowing IH stained for SREBP2 (magenta), SOX18 (cyan), and the human EC-specific lectin UEA1 (yellow). Cell nuclei are stained with DAPI (blue). SOX18 + /SREBP2 + double positive cell nuclei (arrowheads) are significantly more abundant in proliferating phase and appear increased in regrowing compared to involuting phase IH and age-matched skin controls, as quantified in (E). P values were calculated using one-way ANOVA with Šidák-correction. Data show the mean ± SD. Data represent sample sizes for n=4 age-matched skin controls, n= 10 each for proliferating and involuting phase IH, and n=2 for regrowing IH. Scale bars 50 μm.
Overview of patient cells and tissues used throughout the study
An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma

February 2024

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62 Reads

Infantile hemangioma (IH) is the most common tumor in children and a paradigm for pathological vasculogenesis, angiogenesis and regression. Propranolol is the mainstay of treatment for IH. It inhibits hemangioma vessel formation via a β-adrenergic receptor independent off-target effect of its R(+) enantiomer on the endothelial specific transcription factor sex-determining region Y (SRY) box transcription factor 18 (SOX18). Transcriptomic profiling of patient-derived hemangioma stem cells uncovered the mevalonate pathway (MVP) as a target of R(+) propranolol. Loss of SOX18 function confirmed R(+) propranolol mode of action on the MVP. Functional validation in preclinical IH models revealed that statins - targeting the MVP - are potent inhibitors of hemangioma vessel formation. We propose a novel SOX18-MVP-axis as a central regulator of IH pathogenesis and suggest statin repurposing to treat IH. Our findings reveal novel pleiotropic effects of beta-blockers and statins acting on the SOX18-MVP axis to disable an endothelial specific program in IH, which may impact other scenarios involving pathological vasculogenesis and angiogenesis. Graphical abstract


Fig. 2. Patient 4 at (a) 3 months, (B) 14 months, (c) 3.5 years, (D) 7 years, and (e) 11 years of age. the patient received systemic corticosteroid at ages 2-8 months and multiple treatments with pulsed dye laser at 6-10 years. at 17 years, evaluated by plastic surgery: left nipple ptosis (1 cm), but breast volume within normal range of symmetry.
Fig. 3. Patient 7 at (a) 4 years, (B) 5 years, (c), 7 years, and (D) 14 years of age. Patient received subtotal excision of involuted hemangioma at age 5 years. right breast implant placed at age 14 years, persistent hypoplasia of right breast at 36 years.
Characteristics of Patients with Breast IH
Infantile Hemangioma of the Breast: Long-Term Assessment of Outcomes

January 2024

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138 Reads

Background The literature is meager regarding the natural history and outcomes of infantile hemangiomas (IHs) in the breast. Treatment in childhood may be considered due to psychosocial and physical concerns with breast development. Early surgical intervention may cause iatrogenic breast asymmetry and possibly impair lactation later in life. This study characterizes the clinical presentation, management, and long-term outcomes of IHs arising in the breast. Methods Female patients aged 11 years or older at presentation were included in a retrospective review of the Vascular Anomalies Center database for patients with IHs of the breast seen at our institution between 1980 and 2020. Breast development was ascertained by a structured telephone interview, physical examination, or photographs. Results A total of 10 patients met criteria for inclusion in this study. The median age at enrollment was 14 years (11–36 years). Breast asymmetry was noted in 60% of patients (n = 6). Of the four patients who underwent subtotal excision of breast IH, three developed ipsilateral breast hypoplasia. Breast asymmetry was also noted in three of five patients who did not receive medical treatment: two with hypoplasia and one with hyperplasia. No asymmetry was noted in the single patient who received corticosteroid. Conclusions IHs involving the nipple–areola complex can be associated with breast asymmetry. Hypoplasia was noted in patients not treated with corticosteroid or resection in childhood. These findings suggest that systemic treatment should be considered. Longitudinal follow-up on patients treated with propranolol will elucidate its possible benefits in minimizing breast asymmetry.


Spectrum of lymphatic anomalies in patients with RASA1 ‐related CM‐AVM

September 2023

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30 Reads

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6 Citations

Pediatric Dermatology

Background Capillary malformation‐arteriovenous malformation (CM‐AVM) is characterized by multifocal fast‐flow capillary malformations, sometimes with arteriovenous malformations/fistulas, skeletal/soft tissue overgrowth, telangiectasias, or Bier spots. Lymphatic abnormalities are infrequently reported. We describe seven patients with CM‐AVM and lymphatic anomalies. Methods Following IRB approval, we identified patients with CM‐AVM and lymphatic anomalies seen at the Vascular Anomalies Center at Boston Children's Hospital from 2003 to 2023. We retrospectively reviewed records for clinical, genetic, laboratory, and imaging findings. Results We found seven patients with CM‐AVM and lymphatic abnormalities. Five patients were diagnosed prenatally: four with pleural effusions (including one suspected chylothorax) and one with ascites. Pleural effusions resolved after neonatal drainage in three patients and fetal thoracentesis in the fourth; however, fluid rapidly reaccumulated in this fetus causing hydrops. Ascites resolved after neonatal paracentesis, recurred at 2 months, and spontaneously resolved at 5 years; magnetic resonance lymphangiography for recurrence at age 19 years suggested a central conducting lymphatic anomaly (CCLA), and at age 20 years a right spermatic cord/scrotal lymphatic malformation (LM) was detected. Chylous pericardial effusion presented in a sixth patient at 2 months and disappeared after pericardiocentesis. A seventh patient was diagnosed with a left lower extremity LM at 16 months. Six patients underwent genetic testing, and all had RASA1 mutation. RASA1 variant was novel in three patients (c.1495delinsCTACC, c.434_451delinsA, c.2648del), previously reported in two (c.2603+1G>A, c.475_476del), and unavailable in another. Median follow‐up age was 5.8 years (4 months–20 years). Conclusion CM‐AVM may be associated with lymphatic anomalies, including pericardial/pleural effusions, ascites, CCLA, and LM.


Citations (74)


... IHs are the most prevalent benign vascular tumors observed in infants, affecting approximately 4-5% of newborns [1]. They follow a distinctive clinical trajectory, characterized by an initial proliferative phase that is subsequently followed by spontaneous involution. ...

Reference:

Rapidly Growing Ulcerating Infantile Hemangioma Characterized by Leukocytosis and Thrombocytosis in an Infant
Infantile hemangioma: the common and enigmatic vascular tumor

The Journal of clinical investigation

... In experiment A, Tween 80 was used at concentrations of 1.6 × 10 −5 , 10 −4 g/mL, 10 −3 , 5 × 10 −3 g/mL, and 10 −2 g/mL. The fractional volumes of ethanol used were 40,42,44,46,48,50,52,54,56,58, and 60%. In experiment B, the concentrations of PC 80 were 10 −2 g/mL, 1.5 × 10 −2 g/mL, and 2 × 10 −2 g/mL. ...

Spectrum of lymphatic anomalies in patients with RASA1 ‐related CM‐AVM
  • Citing Article
  • September 2023

Pediatric Dermatology

... Nasendoscopy offers real-time imaging but can be limited by fiberoptic distortion and patient compliance (Mason & Black, 2023;Perry et al., 2018). Videofluoroscopy can provide visualization during speech production, including lateral, town, and anterior planes (Dudas et al., 2006;Sullivan et al., 2023). MRI offers superior threedimensional (3D) imaging of intrinsic VP musculature in any plane (Bae et al., 2011;Mason & Perry, 2017). ...

Videofluoroscopy Versus Nasopharyngoscopy of Lateral Pharyngeal Wall Movement for Assessment of Velopharyngeal Insufficiency
  • Citing Article
  • August 2022

The Journal of craniofacial surgery

... In humans, the central lymphatics include the cisterna chyli -where the lower extremity peripheral lymphatics and intra-abdominal lymphatics is characterized by the invasion of lymphatic vessels into organs, such as the spleen, medullary bone, and the surrounding soft tissue due to the abnormal proliferation of LECs (49). KLA has some phenotypic overlap with GLA but is defined by the unique spindle-shaped morphology of affected LECs on biopsy (49)(50)(51). Mediastinal involvement as well as pericardial effusions may also be prevalent (52). KLA has a high morbidity due to the severity of the lesions (53). ...

Kaposiform Lymphangiomatosis: Pathologic Aspects in 43 Patients
  • Citing Article
  • April 2022

The American Journal of Surgical Pathology

... The total incubation time was 240 h. The sampling procedure consisted of the following steps ( Figure 8): taking 400 µL of test solution from reaction systems containing no ionic liquid (1)(2)(3)(4)(5)(6)(7)(8) and 50 µL of test solution from reaction systems containing ionic liquids (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24); the samples were placed in a speed vac until the volatile solvents were completely evaporated; 200 µL of acetonitrile was added to each of the 24 samples, set in a shaker for 15 min and centrifuged for 15 min at 20 • C at 18,000 rpm in the next step; the supernatant obtained after centrifugation was then transferred to the glass insert vials and analyzed via UPLC-IT-TOF. ...

Non-β-blocker enantiomers of propranolol and atenolol inhibit vasculogenesis in infantile hemangioma

The Journal of clinical investigation

... Minor nasal revisions were required in 56.26% of patients (Table 2). Yao and Mulliken reported 65% of nasal revisions after primary cleft nose repair in unilateral cleft patients, 14 whereas Salyer et al 15 observed a lower revision rate at 35%. Kane et al reported a secondary rhinoplasty rate of 30%-40%. ...

The Unilateral Cleft Lip Nasal Deformity: Revisions within 20 Years after Primary Correction
  • Citing Article
  • May 2021

Plastic & Reconstructive Surgery

... Diagnosis is confirmed by GLUT-1 (25%-75% immunopositive channels); D2-40 (1%-25% channels); and Prox-1 (1%-50% of channels) on IHC. [54] The clinical mimics include angiokeratoma and LMs, which are frequently misdiagnosed. Predominant dermoscopic features include red to reddish-purple dots, globules, and structureless areas. ...

Verrucous Venous Malformation-Subcutaneous Variant
  • Citing Article
  • April 2021

American Journal of Dermatopathology

... The knee is the most frequent reported location of IAVM, accounting for 60 % of all cases [1,5]. In a large cohort of non-syndromic lower extremity IAVM, knee involvement was observed in 97/156 (62 %) patients [10]. IAVMs seem overall rare, as this lesion was found in only one of 4682 knee arthroscopies [11]. ...

Classification of lower extremity venous malformations and risk of knee involvement: A retrospective cohort study
  • Citing Article
  • January 2021

Journal of the American Academy of Dermatology

... Unfortunately, since numerous items can be measured and measurements are complicated, many studies that have used three-dimensional imaging have only described the numerical evaluation of the same measurement items as direct measurement, without setting a reference point or a reference line. Actually, only a few studies have evaluated facial components three-dimensionally 25,26) . Prior to this study, we were not able to find reports that referred to the height differences in the labial commissure or the inclination of the lip using direct measurement, standard photographs, or three-dimensional photographs. ...

Philtral Ridge Projection in Repaired Unilateral Cleft Lip: Three-Dimensional Anthropometry
  • Citing Article
  • October 2020

Plastic & Reconstructive Surgery

... 5 Venous malformations are the most common form of vascular malformation, and affect approximately 1% of the population. [6][7][8] They are present at birth and enlarge as the child grows. Evidence suggests that due to hormonal influences, venous malformations accelerate their growth during puberty and pregnancy as well. ...

Diffuse Venous Malformations of the Upper Extremity (Bockenheimer Disease): Diagnosis and Management
  • Citing Article
  • September 2020

Plastic & Reconstructive Surgery